Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy.
Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy.
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线粒体丙酮酸载体丰度介导病理心脏肥大。
DOI：
10.1038/s42255-020-00276-5
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发表时间：
2020-11
影响因子：
20.8
通讯作者：
Eaton P
中科院分区：
文献类型：
--
作者：
Fernandez-Caggiano M;Kamynina A;Francois AA;Prysyazhna O;Eykyn TR;Krasemann S;Crespo-Leiro MG;Vieites MG;Bianchi K;Morales V;Domenech N;Eaton P
心肌细胞依赖代谢底物，不仅为心输出量提供能量，还在应激期间促进生长和重塑。在这里，我们显示线粒体丙酮酸载体(MPC)的丰度介导病理性心肌肥厚。肥大衰竭的人类心脏以及血管紧张素II或横动脉缩窄所致衰竭的小鼠的心肌中，MPC的丰度降低。小鼠心肌细胞MPC1/2的结构性敲除导致心肌肥大和存活率下降，而他莫昔芬诱导的心肌细胞特异性MPC1/2减少到压力超负荷时观察到的减弱水平，足以诱导心肌肥厚并损害心功能。来自心肌细胞限制性基因敲除小鼠的衰竭心脏表现出更丰富的合成代谢产物，包括氨基酸和戊糖磷酸途径中间体和还原辅因子。补充的1，2-13C2-葡萄糖示踪剂研究证实，这些心脏显示流入线粒体三羧酸循环中间体的碳流量随之减少。相反，可诱导的心肌细胞过表达MPC1/2导致三羧酸循环中间产物增加，并在横动脉缩窄过程中持续表达载体，以防止心肌肥大和衰竭。总而言之，我们证明MPC1/2的丢失是导致心脏重构不良的原因。
Cardiomyocytes rely on metabolic substrates, not only to fuel cardiac output, but also for growth and remodeling during stress. Here we show that Mitochondrial Pyruvate Carrier (MPC) abundance mediates pathological cardiac hypertrophy. MPC abundance was reduced in failing hypertrophic human hearts, as well as the myocardium of mice induced to fail by angiotensin II or transverse-aortic constriction-induced. Constitutive knockout of cardiomyocyte MPC1/2 in mice resulted in cardiac hypertrophy and reduced survival, while tamoxifen-induced cardiomyocyte-specific reduction of MPC1/2 to the attenuated levels observed during pressure-overload was sufficient to induce hypertrophy with impaired cardiac function. Failing hearts from cardiomyocyte-restricted knockout mice displayed increased abundance of anabolic metabolites, including amino acids and pentose phosphate pathway intermediates and reducing cofactors. These hearts showed a concomitant decrease in carbon flux into mitochondrial tricarboxylic acid cycle intermediates, as corroborated by complementary 1,2-13C2-glucose tracer studies. In contrast, inducible cardiomyocyte overexpression of MPC1/2 resulted in increased tricarboxylic acid cycle intermediates, and sustained carrier expression during transverse-aortic constriction protected against cardiac hypertrophy and failure. Collectively, we demonstrate that loss of the MPC1/2 causally mediates adverse cardiac remodelling.
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影响因子：
21.3
作者：
Flores A;Schell J;Krall AS;Jelinek D;Miranda M;Grigorian M;Braas D;White AC;Zhou JL;Graham NA;Graeber T;Seth P;Evseenko D;Coller HA;Rutter J;Christofk HR;Lowry WE
通讯作者：
Lowry WE
影响因子：
20.8
作者：
McCommis KS;Kovacs A;Weinheimer CJ;Shew TM;Koves TR;Ilkayeva OR;Kamm DR;Pyles KD;King MT;Veech RL;DeBosch BJ;Muoio DM;Gross RW;Finck BN
通讯作者：
Finck BN
影响因子：
--
作者：
ALLARD, MF;SCHONEKESS, BO;LOPASCHUK, GD
通讯作者：
LOPASCHUK, GD
影响因子：
37.8
作者：
KAGAYA, Y;KANNO, Y;TAKISHIMA, T
通讯作者：
TAKISHIMA, T
影响因子：
3.1
作者：
Barger, PM;Kelly, DP
通讯作者：
Kelly, DP